Malaria is estimated to kill more than one million people annually, especially among children under six years of age. As a result of the resurgence of malaria and increased resistance to prevalent anti-malaria agents such as chloroquine, there is an urgent need for new efficient chemotherapeutics against this disease. Drug development has shifted toward targeting specific proteins that are unique and critical for cellular growth and survival of the parasite. Recently, the presence of a mevalonate-independent pathway for isoprenoid biosynthesis in Plasmodium falciparum was discovered. 1-deoxy-D-xylulose-5-phosphate (hereinafter abbreviated as DOXP) reducto-isomerase plays an essential role in this non-mevalonate pathway, which is absent in humans. Previous studies demonstrated that fosmidomycin exerts potent anti-malaria activity by inhibition of DOXP reducto-isomerase (hereinafter abbreviated as DXR), the second enzyme in the reaction cascade. In recent clinical trials conducted in Gabon and Thailand, fosmidomycin proved to be efficient in the treatment of patients suffering from acute, uncomplicated Plasmodium falciparum malaria. Fosmidomycin however has the disadvantages of a short plasma half-life and a moderate resorption rate. The acetyl derivative of fosmidomycin, also known as FR900098, was shown to be approximately twice more active than fosmidomycin against Plasmodium falciparum in vitro as well as in a Plasmodium vinckei mouse model.
British Patent No. 1,467,304 discloses N-(3-aminopropyl)-aminoalkane-phosphonic acid esters having the structural formula:    (PO3R1R2)—(CR3R4)—(CH2)a—(CHR6)b—CHR5—NH—(CH2)3—NH2 wherein R1 and R2 are both alkyl, a=0-2 and b=0-1, which are made by reacting an aminoalkanephosphonic acid ester having the structural formula:    (PO3R1R2)—(CR3R4)—(CH2)a—(CHR6)b—CHR5—NH2 with acrylonitrile, followed by catalytic hydrogenation.
U.S. Pat. No. 6,638,957 discloses compounds wherein the nitrogen atom of a 5- to 7-membered nitrogen-oxygen heterocycle is linked to an organophosphorus group POR9R10 (wherein each of R9 and R10 may be hydrogen) via a linker B being an alkenylene group optionally substituted with hydroxy, halogen or oxo. U.S. Pat. No. 6,638,957 additionally discloses 4 individual compounds where a p-substituted phenyl group is present in a position of the organophosphorus group.
U.S. Pat. No. 6,680,308 discloses organophosphorous compounds having the structural formula R1R2N-A-POR3R4 wherein:                each of R1 and R2 may be hydrogen, alkyl, hydroxyalkyl, alkenyl, alkynyl, aryl, acyl, cycloalkyl, aralkyl, heterocyclic, halogen, OX1 or OX2,        each of X1 and X2 may be hydrogen, alkyl, hydroxyalkyl, alkenyl, alkynyl, aryl, acyl, cycloalkyl, aralkyl or heterocyclic,        A is alkylene, alkenylene or hydroxyalkylene, and        each of R3 and R4 may be hydrogen, alkyl, hydroxyalkyl, alkenyl, alkynyl, aryl, acyl, cycloalkyl, aralkyl, heterocyclic or halogen.A is preferably a chain of 3 carbon atoms, and acyl may originate from a carboxylic, carbonic, carbamic or imidic acid or thioacid. In particular, U.S. Pat. No. 6,680,308 discloses:        3-(N-hydroxyamino)-propylphosphonic acid diethylester,        3-(N-hydroxyamino)-propylphosphonic acid,        3-(N-formylhydroxyamino)-propylphosphonic acid diethylester,        3-(N-acetylhydroxyamino)-propylphosphonic acid diethylester,        3-(N-formylhydroxyamino)-propylphosphonic acid monosodium salt, and        3-(N-acetylhydroxyamino)-propylphosphonic acid monosodium salt.        
U.S. Pat. No. 6,534,489 discloses organo-phosphorous compounds having the structural formula R1R2N-A-POR3R4 wherein:                each of R1, R2, R3 and R4 is as defined in U.S. Pat. No. 6,680,308, and        A is a C2-5 alkylene group substituted with at least one C3-8 cycloalkyl-C0-9 alkyl group.The only individual species exemplified in U.S. Pat. No. 6,534,489 are those wherein:        A is a trimethylene group substituted, but not in a position of the organophosphorus group, with phenylethyl, cyclohexylethyl or pyridylethyl        R1 is acetyl, and        R2 is hydroxy.        
WO 2005/048715 discloses organophosphorous compounds having the structural formula R1R2N—CH2)2—CHCy-POR3R4 wherein:                Cy is a (optionally substituted with alkyl, alkoxy, cycloalkyl-C0-9 alkyl, cycloalkyl-C0-9 alkyloxy, acyl, hydroxy, halogen or trifluoromethyl) C5-8 mono- or bi-cyclic cycloalkyl group, wherein said cycloalkyl group may be unsaturated with one or more double or triple bonds and wherein 1 to 4 carbon atoms of said cycloalkyl group may be replaced with N, O or S; and        each of R1 and R2 may be hydrogen, amino, alkyl, alkoxy, cycloalkyl, cycloalkyl-C0-9 alkyl, cycloalkyl-C0-9 alkyloxy, acyl, heterocyclic, hydroxy, halogen, trifluoromethyl, NHX1, NHX2, OX1 or OX2, but and R2 are not both hydrogen,        each of R3 and R4 may be hydrogen, alkyl, alkoxy, cycloalkyl, acyl, cycloalkyl-C0-9 alkyl, cycloalkyl-C0-9 alkyloxy, heterocyclic, hydroxy, halogen, trifluoromethyl, OX3 or OX4, and        each of X1, X2, X3 and X4 may be hydrogen, halogen, alkyl, cycloalkyl, cycloalkyl-C0-9 alkyl, cycloalkyl-C0-9 alkyloxy or heterocyclic.The cycloakyl group Cy may be aromatic and such aromatic cyclic group may further include substituents such as nitro, trifluoromethyl and phenyl residues; particularly preferred are aromatics substituted with one or more alkyl groups such as methyl, ethyl, propyl or isopropyl. Other preferred cycloalkyl groups include furanyl (page 10 line 2), indolyl and benzidinyl.        
Individual species described in WO 2005/048715 together with their biological data include the following:                α-phenyl-fosmidomycin diethanolammonium salt,        α-phenyl-FR900098 diethanolammonium salt,        [3-(hydroxy-formyl-amino)-1-(p-fluorophenyl)-propyl] phosphonic acid di-(2,2-dimethylpropionic acid) ester,        [3-(hydroxy-formyl-amino)-1-(o-fluorophenyl)-propyl] phosphonic acid di-(2,2-dimethylpropionic acid) ester,        [3-(hydroxy-formyl-amino)-1-(o,p-dichlorophenyl)-propyl] phosphonic acid di-(2,2-dimethylpropionic acid) ester,        [3-(hydroxy-formyl-amino)-1-(o,o-dichlorophenyl)-propyl] phosphonic acid di-(2,2-dimethylpropionic acid) ester,        [3-(hydroxy-formyl-amino)-1-(o-toluoyl)-propyl] phosphonic acid di-(2,2-dimethylpropionic acid) ester,        [3-(hydroxy-formyl-amino)-1-(p-toluoyl)-propyl] phosphonic acid di-(2,2-dimethylpropionic acid) ester,        [3-(hydroxy-formyl-amino)-1-(o,o-xylyl)-propyl] phosphonic acid di-(2,2-dimethylpropionic acid) ester,        [3-(hydroxy-formyl-amino)-1-(p-biphenyl)-propyl] phosphonic acid di-(2,2-dimethylpropionic acid) ester,        [3-(benzyloxy-formyl-amino)-1-naphthyl-propyl] phosphonic acid di-(2,2-dimethylpropionic acid) ester,        [3-(benzyloxy-formyl-amino)-1-phenyl-propyl] phosphonic acid diethyl ester,        [3-(benzyloxy-acetyl-amino)-1-phenyl-propyl] phosphonic acid diethyl ester,        [3-(benzyloxy-formyl-amino)-1-phenyl-propyl] phosphonic acid di-(2,2-dimethylpropionic acid) ester,        [3-(benzyloxy-acetyl-amino)-1-phenyl-propyl] phosphonic acid di-(2,2-dimethylpropionic acid) ester,        [3-hydroxy-formyl-amino)-1-phenyl-propyl] phosphonic acid di-(2,2-dimethylpropionic acid) ester, and        [3-hydroxy-acetyl-amino)-1-phenyl-propyl] phosphonic acid di-(2,2-dimethylpropionic acid) ester.        
The biological data (measured against Plasmodium falciparum strain Dd2) for the 17 above compounds, especially in the Desjardins test procedure, show that:                the IC50 value of α-phenyl-fosmidomycin diethanolammonium salt is 4.5 times less than fosmidomycin, but the IC50 value of α-phenyl-FR900098 diethanol-ammonium salt is higher than FR900098; and        the IC50 value of α-phenyl-fosmidomycin di-(2,2-dimethylpropionic acid) esters is not significantly changed when the α-phenyl group is substituted with one or two fluoro, chloro or methyl groups; it is however disadvantageously increased for the o,o-dichlorophenyl and p-biphenyl substituents.        
Therefore there is a regular need in the art for novel compounds having significant and specific anti-parasitic properties without having the drawbacks of known effective anti-parasitic agents. There is a regular need in the art for effective anti-parasitic agents having improved metabolisation and/or pharmacokinetic behaviour and which therefore can be more easily formulated into effective dosage forms. There is also a need in the art for such novel compounds exhibiting a longer plasma half-life and a significantly improved resorption rate. There is also a need in the art for such novel compounds which can be easily produced in good yield and purity from commercially available materials through a limited number of fully reproducible synthetic process steps.